Neuropeptides present in the hypothalamus play a major role in mediating the control of body weight. (Flier et al., 1998, Cell, 92, 437-440.) Melanin-concentrating hormone (MCH) produced in mammals is a cyclic 19-amino acid neuropeptide synthesized as part of a larger pre-prohormone precursor in the hypothalamus which also encodes neuropeptides NEI and NGE. (Nahon et al., 1990, Mol. Endocrinol. 4, 632-637; Vaughan et al., U.S. Pat. No. 5,049,655; and Vaughan et al., 1989, Endocrinology 125, 1660-1665.) Human MCH (hMCH) has the following structure (SEQ. ID. NO. 1):

MCH was first identified in salmon pituitary, and in fish MCH affects melanin aggregation thus affecting skin pigmentation. In trout and eels MCH has also been shown to be involved in stress induced or CRF-stimulated ACTH release. (Kawauchi et al., 1983, Nature 305, 321-323.) In humans two genes encoding hMCH have been identified that are expressed in the brain. (Breton et al., 1993, Mol. Brain Res. 18, 297-310.) In mammals MCH has been localized primarily to neuronal cell bodies of the hypothalamus which are implicated in the control of food intake, including perikarya of the lateral hypothalamus and zona inertia. (Knigge et al., 1996, Peptides 17, 1063-1073.)
Pharmacological and genetic evidence suggest that the primary mode of MCH action is to promote feeding (orexigenic). MCH mRNA is up regulated in fasted mice and rats, in the ob/ob mouse and in mice with targeted disruption in the gene for neuropeptide Y (NPY). (Qu et al., 1996, Nature 380, 243-247 and Erickson et al., 1996, Nature 381, 415-418.) Injection of MCH centrally (ICV) stimulates food intake and MCH antagonizes the hypophagic effects seen with a melanocyte stimulating hormone (αMSH). (Qu et al., 1996, Nature 380, 243-247.) MCH deficient mice are lean, hypophagic and have an increased metabolic rate. (Shimada et al., 1998, Nature 396, 670-673.) The administration of MCH has been indicated to be useful for promoting eating, appetite or the gain or maintenance of weight. (Maratos-Flier, U.S. Pat. No. 5,849,708.)
MCH action is not limited to modulation of food intake as effects on the hypothalamic-pituitary-axis have been reported. (Nahon, 1994, Critical Rev. in Neurobiol. 8, 221-262.) MCH may be involved in the body response to stress as MCH can modulate the stress-induced release of CRF from the hypothalamus and ACTH from the pituitary. In addition, MCH neuronal systems may be involved in reproductive or maternal function.
Human MCH can bind to at least two different receptors: MCH-1R and MCH-2R. (Chambers et al., 1999, Nature 400, 261-265; Saito et al., 1999, Nature 400, 265-269; Bächner et al., 1999, FEBS Letters 457:522-524; Shimomura et al., 1999, Biochemical and Biophysical Research Communications 261, 622-626; Sailer et al., Proc. Natl. Acad. Sci. 98:7564-7569, 2001.) The amino acid identity between MCH-2R and MCH-1R is about 38%. (Sailer et al., Proc. Natl. Acad. Sci. 98:7564-7569,2001.)